PROJECT SUMMARY/ABSTRACT Despite the availability of effective antiretroviral therapies, cognitive deficits persist in HIV-infected (HIV+) individuals. For example, in the Women's Interagency HIV Study (WIHS), HIV+ virally suppressed (HIV+VS) women showed neurocognitive impairment (NCI) in verbal learning and memory as well as working memory, attention and executive function. These domains of cognitive performance relate to the declarative memory and cognitive control subdomains of the NIMH Research Domain Criteria (RDoC), a framework that has not yet been leveraged to advance understanding of the mechanisms contributing to patterns of NCI in HIV. There is a strong scientific premise that HIV-associated brain injury stems from immunological processes, particularly neuroinflammation, mediated by cells of the monocyte/macrophage lineage. In support of this view, studies by our team and others demonstrate that NCI in HIV is associated with microglial activation and monocyte activation. In this proposal, our multidisciplinary team will provide innovation to this line of inquiry by conducting a longitudinal neuroimaging study that not only uses the RDoC framework but also assesses neuroinflammation. Building on our cross-sectional neuroimaging studies, we will first use task-based functional magnetic resonance imaging (fMRI) and resting state fMRI in HIV+VS individuals and HIV-uninfected individuals to identify the neural circuitry contributing to deficits in declarative memory and cognitive control. Second, we will use positron emission tomography (PET) to assess HIV-related alterations in chronic neuroinflammation in relation to NCI. Third, we will computationally integrate the multimodal imaging data in relation to changes in cognitive performance over time. To achieve our goal, we propose a single-site, longitudinal study in phenotypically well- characterized HIV+VS (N=100) and HIV- controls (N=50) from the WIHS and Multicenter AIDS Cohort Study (MACS). Participants will complete neuroimaging assessments (resting state and task-based fMRI, structural MRI, diffusion-weighted MRI) annually for three years and cognitive assessments every six months over that same time. The longitudinal design allows an assessment of the reproducibility of key findings over time and the sensitivity of these neuroimaging measures to changes in cognitive performance. To examine HIV-related alterations in chronic neuroinflammation, a subset of individuals (total n =42; 24 HIV+VS) will also complete PET assessments using [11C]DPA-713 (DPA). In keeping with NIH research priorities, after 5 years of potential funding, the impact of this R01 on the field will be to inform our understanding of the mechanisms linked to neurological comorbidity and to provide novel, more sensitive neuroimaging biomarkers to guide testing of new cognitive therapies for HIV+ individuals.